Research Project
10269675
Project summary Viral pneumonia is currently among the most common causes of death in the world. Viral pneumonia impairs tissue repair leading to both in-hospital death and prolonged hospital-acquired disability. Understanding and targeting mechanisms that impair tissue repair after viral pneumonia therefore offers promise to both improve survival and prevent multiple organ morbidity after hospital discharge. In this Project and PPG, we hypothesize that ongoing inflammation after the influenza A virus (IAV) is cleared precludes proper lung repair. The cytosolic NOD-like receptor protein-3 (NLRP3)-dependent inflammasome complex initiates production of mature forms of the inflammatory cytokines IL-1? and IL18, inducing recruitment of effector cells to the site of infection that are essential to clearance of the influenza A virus. In addition, inflammasome activation within the monocyte derived alveolar macrophages participates in the ongoing inflammation observed in patients after influenza A virus clearance. Mitochondria have been proposed to be key regulators of NRLP3 dependent inflammasome activation. Our preliminary data demonstrate that inhibition of mitochondrial complex I or III as well as administration of sodium lactate, which does not alter the pH, attenuates inflammasome activation. Furthermore, our preliminary data indicate that monocyte-derived alveolar macrophages upon influenza infection display an increase in mitochondrial pyruvate carrier (MPC) mRNA, which diminishes pyruvate conversion into lactate by lactate dehydrogenase A (LDHA). We will test whether inflammasome dependent inflammation post-viral clearance in mice requires mitochondrial complexes I and III as well as lactate production in monocyte-derived alveolar macrophages using conditional knockout mice. Collectively these hypotheses will be tested in three interrelated Specific Aims: (1) Is mitochondrial complex I generated ROS required for influenza A induced NLRP3-dependent inflammasome activation in monocyte-derived alveolar macrophages? (2) Is mitochondrial complex III produced ROS necessary for influenza A induced NLRP3-dependent inflammasome activation in monocyte-derived alveolar macrophages? (3) Does in vivo lactate production decrease NLRP3-dependent inflammasome activation following influenza A virus infection in monocyte-derived alveolar macrophages.
